Drug Design, Development and Therapy最新文献

Purpose: Previous studies have reported the recommended dosage of remimazolam alone for achieving loss of consciousness (LoC). However, the effect of analgesics on the dosage of remimazolam for successful sedation remains unclear. This study evaluated the impact of fentanyl on the effective dose of remimazolam-induced sedation in female patients undergoing elective hysteroscopic surgery.

Patients and methods: Two hundred female patients were randomly allocated into two groups, receiving with or without fentanyl (1ug/kg) during anesthetic induction. Within each group, patients were randomized to receive one of four doses (0.1, 0.2, 0.3, and 0.4 mg/kg) of remimazolam for sedation. Modified Observer's Assessment of Alertness/Sedation (MOAA/S) was evaluated during anesthetic induction. Success was defined when the patient did not respond to painful trapezius squeeze and no requirement for rescue doses. Estimate of ED50 and ED95 with 95% confidence interval (CI) was performed by probit regression.

Results: The ED50 and ED95 values of remimazolam for patients receiving fentanyl (1 ug/kg) were 0.097 (95% CI, 0.072-0.120) mg/kg and 0.254 (95% CI, 0.203-0.345) mg/kg, respectively. For patients not receiving fentanyl, the ED50 and ED95 values of remimazolam were 0.181 (95% CI, 0.149-0.215) mg/kg and 0.475 (95% CI, 0.377-0.687) mg/kg, respectively. The estimated relative median potency of remimazolam in patients, with and without fentanyl administration, was determined to be 0.534 (95% CI, 0.327-0.737).

Conclusion: The administration of fentanyl reduced the effective dose of remimazolam-induced sedation by 50% in female patients undergoing elective hysteroscopic surgery. The recommended ED95 dose for remimazolam-induced sedation was 0.254 mg/kg under the condition of this study.

Trial number and registry url: ChiCTR2400079842; https://www.chictr.org.cn/showproj.html?proj=216480: HUANG, Date of registration: January 15, 2024.

Purpose: There were two main purposes for this study. One, to report two benzbromarone analogs and test their in vitro activity in the URAT1 inhibition assay; and two, to probe the structure-activity relationship (SAR) of various benzbromarone analogs regarding other drug transporters that may play a role in the uric acid uptake/elimination interplay.

Methods: In brief, chemical synthesis of two benzbromarone analogs was prepared using methods analogous to those reported. Furthermore, drug transporter protein inhibition was investigated in vitro using oocytes expressing hURAT1, hURATv1 (GLUT9), hOAT1, hOAT3, hOAT10, hNPT4, OATP1B1, OATP1B3 and OATP2B1 prepared and utilized to conduct inhibition studies. In addition, one novel benzbromarone analog was studied via in vivo rat pharmacokinetic experiments to determine apparent oral bioavailability.

Results: Two analogs, 6-fluoro-benzbromarone (5) and 5,6-difluoro-benzbromarone (9), were synthetically prepared and 5 had a hURAT1 IC₅₀ inhibition of 18 ± 4 nM, while analog (9) had an IC₅₀ of 245 ± 64 nM. Analog (5) had good oral bioavailability (F_a) >0.6 in rat. Eadie-Hofstee plot and double-reciprocal plot of the Michaelis-Menten equation are summarized for benzbromarone (2) and its major Phase I metabolite 6-hydroxy-benzbromarone (3).

Conclusion: These results illustrate that the K_m for [¹⁴C]UA uptake was not altered in the presence of 2 or 3, but rather the V_max was reduced in the presence of inhibitors when added to the uptake solutions. As a result, these data support the notion that 2 and 3 inhibit [¹⁴C]UA uptake by non-competitive inhibition and not at the URAT1 binding site.

In recent years, our understanding of sepsis has greatly advanced. However, due to the complex pathological and physiological mechanisms of sepsis, the mechanisms of sepsis are currently not fully elucidated, and it is difficult to translate the research results into specific sepsis treatment methods. Melatonin possesses broad anti-inflammatory, antioxidant, and immune-regulatory properties, making it a promising therapeutic agent for sepsis. In recent years, further research has deepened our understanding of the potential mechanisms and application prospects of melatonin in sepsis. The mechanisms underlying the protective effects of melatonin in sepsis are multifaceted. In this review, based on a substantial body of clinical trials and animal research findings, we first highlighted the significance of melatonin as an important biomarker for disease progression and prognosis in sepsis. We also described the extensive regulatory mechanisms of melatonin in sepsis-induced organ damage. In addition to its broad anti-inflammatory, and anti-oxidant effects, melatonin exerts positive effects by regulating metabolic disorders, hemodynamics, cell autophagy, cellular ion channels, endothelial cell permeability, ferroptosis and other complex pathological mechanisms. Furthermore, as a safe exogenous supplement with low toxicity, melatonin demonstrates positive synergistic effects with other anti-sepsis agents. In the face of the urgent medical challenge of transforming the increasing knowledge of sepsis molecular mechanisms into therapeutic interventions to improve patient prognosis, melatonin seems to be a promising option.

Objective: To study the safety and efficacy of sevoflurane pretreatment in preventing sufentanil-induced cough in children and to compare its antitussive effect with that of butorphanol, an opioid analgesic that has been proven effective in clinical trials.

Data and methods: This was a prospective randomized controlled trial. A total of 174 patients who underwent ENT surgery at Chaohu Hospital Affiliated with Anhui Medical University were enrolled and divided into groups S, C and B, with 58 patients in each group, according to the random number table method. General anesthesia was induced with 5% sevoflurane in Group S, 2.5 mg/kg of propofol and 30 μg/kg of butorphanol in Group B, and 2.5 mg/kg of propofol and 1 mL of normal saline in Group C. The cough grade, intraoperative hemodynamic data, blood oxygen saturation, and adverse reactions within 24 h after the operation were recorded.

Results: The overall cough grade significantly differed among the 3 groups (P<0.05). Compared with those of Group C, the cough grades of Groups S and B were significantly lower (P<0.05). There was no significant difference in the cough grade between Group S and Group B (P>0.05). Groups S and B cannot be considered equivalent. There were no significant differences in the MAP, HR, SpO2 or BIS value among the three groups at different time points (P>0.05). There was no significant difference in the incidence of postoperative nausea, vomiting, dizziness or chills among the 3 groups (P>0.05).

Conclusion: Induction of anesthesia using 5% sevoflurane to reduce Bis to 60 in children significantly reduces the probability of sufentanil-induced coughing (SIC) without significant hemodynamic fluctuations.

Purpose: Human interleukin-2 (IL-2) stimulates the differentiation and expansion of diverse immune cells dose-dependently. As an immunotherapy agent to treat metastatic cancers, IL-2 has been used in clinical practice and has demonstrated clear antitumor effects; however, its short half-life, the risk of capillary leak syndrome, and the unintended activation of immunosuppressive T_reg cells hinder its clinical application. To address these challenges, a novel PEGylated interleukin-2 analogue, SHR-1916, was designed. Its cellular selectivity, efficacy, and improved pharmacokinetic profiles were investigated.

Methods: The binding affinities were characterized by surface plasmon resonance (SPR) in vitro. Subsequently, the stimulatory properties were investigated in a murine cell line (CTLL-2), a human cell line (M07e), and human peripheral blood mononuclear cells (PBMCs). To assess the anti-tumor efficacy, a CT-26 colon carcinoma syngeneic model in BALB/c mice and a A375 human melanoma xenograft model using PBMC humanized NCG mice were used in vivo. Moreover, the pharmacokinetic behavior following a single intravenous or subcutaneous dose was evaluated in Sprague-Dawley rats.

Results: SHR-1916 abolished binding to its receptor IL-2Rα, as evidenced by SPR assays, and exerted its activity mainly through binding to IL-2Rβγ, as confirmed by CTLL-2 and M07e cell proliferation assays. In contrast to IL-2, SHR-1916 exhibited a more biased activation of CD8⁺ T and NK cells compared to T_reg cells and stimulated an increase in IFNγ secretion in PBMCs dose-dependently without triggering the release of other potential side effect-associated cytokines. In CT26 colon carcinoma and A375 melanoma models, SHR-1916 significantly reduced the tumor burden. Pharmacokinetic results showed that SHR-1916 had a significantly prolonged half-life in rats.

Conclusion: SHR-1916 exhibited excellent cellular selectivity, anti-tumor efficacies, and improved pharmacokinetics. It has the potential to serve as a novel immunotherapeutic agent designed to enhance IL-2's immune-stimulating activities and promote its tolerability while reducing the immunoregulatory function of T_reg cells.

Objective: This study aimed to investigate the mechanisms and specific targets of cordycepin in the treatment of renal fibrosis using a unilateral ischemia-reperfusion (UIR) model.

Methods: A UIR mouse model was established, followed by intraperitoneal injections of cordycepin and Mdivi-1. Masson's trichrome staining and PAS staining were used to identify renal tubulointerstitial fibrosis and assess the degree of renal injury. Fibrosis markers and mitochondrial dynamics-related proteins were evaluated using Western blotting, while differential gene expression and pathway enrichment were analyzed by RNA-seq. Molecular docking, molecular dynamics simulations and surface plasmon resonance were conducted to validate the specific binding sites of cordycepin on the target protein Drp1. Immunofluorescence and in vitro experiments further elucidated the therapeutic mechanism of cordycepin.

Results: In vivo experiments showed that intraperitoneal injection of cordycepin significantly reduced renal inflammation and fibrosis, lowered serum creatinine levels, and decreased collagen deposition. Transcriptome analysis revealed that cordycepin treatment downregulated the mitochondrial fission pathway and upregulated the mitochondrial fusion pathway. Western blotting showed reduced levels of fibrosis markers α-SMA and FN, as well as downregulation of Drp1, MFF, and Fis1, and upregulation of OPA1 and Mfn2. In vitro, cordycepin inhibited TGF-β-induced injury in NRK-52E cells, reducing Drp1 expression and IL-6 secretion. Crosstalk experiments confirmed that decreased IL-6 levels were crucial for cordycepin anti-fibrotic effects by suppressing fibroblast activation.

Conclusion: Cordycepin ameliorates renal fibrosis by targeting Drp1 to inhibit mitochondrial fission in injured renal tubular epithelial cells, reducing IL-6 secretion and inhibiting fibroblast activation.

Purpose: Sufentanil is a potent opioid analgesic frequently used to suppress the tracheal intubation response. The pathophysiological changes of obesity may affect opioid pharmacokinetics and increase the risk of opioid-induced adverse effects. Dexmedetomidine as an adjunct to anesthetic induction could save the dosage of sufentanil and attenuate hemodynamic response to tracheal intubation. This study was aimed at investigating the effect of intravenous dexmedetomidine premedication on the median effective concentration (EC50) of sufentanil for tracheal intubation in obese patients.

Patients and methods: Fifty obese patients undergoing elective bariatric or non-bariatric surgery under general anesthesia with tracheal intubation were equally randomized into the dexmedetomidine group and the saline group. Depending on the group, the patients were intravenously premedicated with 1 μg/kg dexmedetomidine or saline before anesthesia induction. Anesthesia was induced with target-controlled infusion of propofol (at 3.5 μg/mL) and sufentanil. The effect-site concentration of sufentanil for the first patient in the two groups was set at 0.4 ng/mL. The concentration of sufentanil for the next patient was determined using Dixon's up-and-down sequential method with an interval of 0.05 ng/mL, according to the responses of the previous patient. Hemodynamic variables and sufentanil dose were recorded. The EC50 and 95% confidence interval (CI) of sufentanil were determined using probit regression analysis.

Results: The EC50 of sufentanil and 95% CI were 0.25 (95% CI, 0.17-0.31) ng/mL in the dexmedetomidine group and 0.43 (95% CI, 0.34-0.46) ng/mL in the saline group (P < 0.05). The dosage of sufentanil was significantly lower in the former than in the latter. The hemodynamics were stable in both groups during the study.

Conclusion: Intravenous premedication with 1 μg/kg dexmedetomidine significantly decreased the EC50 of sufentanil and sufentanil requirement for tracheal intubation in obese patients.

Background: During medium- to long-duration spaceflights, real-time microgravity can increase the health risks of astronauts. In particular, the disruption of intestinal homeostasis is closely related to other health problems, and it is necessary to monitor related treatment strategies. Ginseng is a well-known Chinese herbal medicine often used to maintain health. Ginseng total saponins (GTSs), which are the bioactive components of ginseng, have been reported to regulate immune homeostasis, anti-inflammation, and anti-oxidation. This study focused on the regulation of GTSs in intestinal homeostasis imbalance caused by microgravity.

Methods: A hindlimb suspension (HLS) rat model was established to evaluate the intestinal protective effects of GTSs. Differentially expressed genes (DEGs) were screened using RNA-Seq. RT-PCR was performed to further focus and verify these results. The gut microbiome composition was examined based on 16S rRNA gene amplicon sequencing, and the short-chain fatty acids produced were further analyzed.

Results: We found that GTSs intervention effectively improved the intestinal injury caused by simulated weightlessness, including reducing the pathological damage, increasing the expression of tight junction proteins and reducing the levels of inflammatory factors. Moreover, GTSs treatment significantly restored the levels of intestinal immunity-related genes and remodeled the gut microbiota. In particular, GTSs significantly increased the abundance of short-chain fatty acid metabolism-related bacteria, thereby increasing the level of propionic acid, butyric acid, isobutyric acid.

Conclusion: Our results revealed that GTSs improved intestinal microecological disorders and impaired immune function caused by the weightlessness simulation. The underlying mechanism may be related to the "intestinal immune -microbiota-metabolic" pathway. These findings provide a theoretical basis for the precise design and development of GTSs for space-health products.

Purpose: To explore and analyze the current research progress, hotspots, and future trends in oliceridine research using bibliometric methods.

Patients and methods: We searched the Web of Science (WOS) database utilizing the keywords TS = ("oliceridine*" OR "TRV 130*" OR "TRV-130*" OR "olinvyk*" OR "TRV130*" OR "C22H31CIN2O2S*") for relevant research literature on oliceridine from its inception to June 16, 2024. Bibliometric methods were applied, and analysis software such as VOSviewer and CiteSpace were used to visualize the publication timeline, authors, countries and regions, keywords, sources of literature, research hotspots, and co-cited documents related to oliceridine. Co-occurrence and aggregation analyses were conducted, and maps relevant to institutional cooperation were generated.

Results: A total of 151 relevant articles were retrieved and included in the final analysis. Most articles were published between 2020 and 2021. The United States has the highest number of publications and citations in this field. Molecular structure development is a pivotal point in this field. Research hotspots were diverse, including acute pain, opioid receptors, β-arrestin, postoperative pain, therapeutic window, respiratory depression, clinical trials, and chronic pain.

Conclusion: Oliceridine, a newly developed analgesic, has garnered global interest. The USA is a leading contributor to this field. Recent research has shifted from basic studies to clinical practice.